Figure 1. The PI3K/Akt Signaling Pathway Is Downstream of Many Important Receptor Tyrosine Kinases, as Well as G-Protein–Coupled Receptors
Figure 2. Organization of the Class I PI3K Family Into Subclasses (IA and IB), as Well as Isoforms
Table. Management Recommendations for Unusual Nonautoimmune and Noninfectious Toxicities Seen With PI3K Inhibitors
The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms. Despite the therapeutic benefit, there have been concerns about the severe and sometimes fatal adverse effects of this class of drug. Several side effects are unusual and have poorly understood mechanisms; these include autoimmune dysfunction, opportunistic infections, skin toxicity, hypertension, and hyperglycemia. An understanding of these unusual toxicities, as well as a good grasp of management principles, will be important as more PI3K inhibitors are approved and become incorporated into routine practice.
The phosphatidylinositol 3-kinase (PI3K) family consists of highly conserved enzymes that are a part of the intracellular PI3K/Akt/mammalian target of rapamycin (mTOR) signaling axis. This axis transmits cell surface receptor signals and affects a variety of tissue-dependent cellular functions. The PI3K/Akt/mTOR axis has been implicated in a variety of cancers, and the pathway is found to be constitutively activated in many B-cell malignancies.[2,3] Importantly, in both normal and malignant B cells, PI3K lies downstream of the B-cell receptor, leading to proliferation via the nuclear factor kappa B pathway (Figure 1). The activation of this pathway provides an attractive target for therapeutic intervention in B-cell malignancies.
In mammals, the PI3K family is divided into three different classes (I, II, and III), and class I PI3K is further subdivided into IA (activated by receptor tyrosine kinases) and IB (activated by G protein–coupled receptors) (Figure 2). Class IA is the subfamily most implicated in human cancer.[1,2,5] Within the PI3K family are four tissue-specific isoforms (Î±, Î², Î´, and Î³) that are associated with various tissue pathways (see Figure 1). The Î±, Î², and Î´ isoforms are all associated with class IA and have a p85 regulatory subunit, while the Î³ isoform is associated with class IB and has a p101 regulatory subunit.[1,6]
The tissue distribution of the different isoforms informs the expected activity and toxicity seen with pharmacologic inhibition of these different PI3K isoforms. PI3K Î± and Î² isoforms are expressed in multiple tissues, while the Î´ isoform is preferentially expressed on leukocytes.[7,8] PI3KÎ± isoforms are expressed ubiquitously and play a critical role in insulin signaling, facts that have relevance for agents currently in development. PI3KÎ³ has been shown to be expressed in many cells of the cardiovascular system.
The Î´ isoform–specific PI3K inhibitor idelalisib has been the most extensively described; however, there are multiple other agents in development targeting various isoforms. Here, we briefly describe the clinical efficacy of these PI3K inhibitors, then discuss the mechanisms and management of the more common unusual toxicities seen with these agents.
Clinical Efficacy and Toxicity to Date
Idelalisib was the first US Food and Drug Administration (FDA)-approved PI3K inhibitor; its use is indicated in relapsed/refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and small lymphocytic lymphoma (SLL). In the phase II study that led to registration, the overall response rate (ORR) for single-agent idelalisib was 54% in FL and 61% in SLL. A phase III study evaluated idelalisib in combination with rituximab in relapsed CLL, with an ORR of 81% that subsequently resulted in combination idelalisib/rituximab being approved for relapsed CLL. In September 2017, the FDA granted copanlisib accelerated approval for use in relapsed FL after two previous lines of therapy. Approval was based on a phase II study of 104 heavily pretreated patients with FL, in which the ORR was 58.7%, with a 14.4% complete response (CR) rate.
While idelalisib has proven to be efficacious for patients with relapsed FL, CLL, and SLL, unexpected autoimmune and infectious toxicities have demonstrated the need for careful development and monitoring of new agents, both alone and in combination with other agents. In a trial in which idelalisib was combined with lenalidomide and rituximab, the Alliance reported unexpected toxicities, including grade 3 or higher transaminitis, hypotension, rash, sepsis syndrome, and pulmonary infiltrates. Of the 8 patients enrolled prior to trial suspension, care in the intensive care unit was required for 3 of them; most toxicities occurred within 3 weeks of initiation of idelalisib. Other studies have also revealed high rates of autoimmune toxicities such as pneumonitis, hepatitis, and noninfectious colitis.[17-21] Increased rates of infection, including opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) infection, have also been seen, with deaths noted from PJP as well as from fungal sinusitis in trials.[13,22] Based on these encountered toxicities, idelalisib now carries a black-box warning regarding hepatotoxicity, diarrhea/colitis, pneumonitis, and intestinal perforation. Use of idelalisib in nonapproved settings is not recommended outside of a clinical trial.[11,23,24]
Phase III testing is currently ongoing for several experimental PI3K inhibitors, including duvelisib (ClinicalTrials.gov identifiers: NCT02049515, NCT02004522) and umbralisib (TGR-1202; NCT02612311, NCT02793583), as well as FDA-approved copanlisib (NCT02367040, NCT02369016, NCT02626455). RP6530, buparlisib (BKM120), and INCB050465 are undergoing earlier-phase testing. A review of current trials and preliminary results has recently been published.
Mechanisms of Immune-Related Toxicity
PI3K inhibition is generally well tolerated when used in a clinically approved setting. However, unusual and unexpected toxicities have been seen with use of PI3K inhibitors during development that are important to keep in mind when considering these agents and when treating patients. These unusual toxicities are best understood in the context of the normal physiology of the PI3K/Akt/mTOR pathway and the tissue distribution of the different PI3K isoforms.
Many of the autoimmune toxicities encountered are likely mediated through the effects of PI3K inhibition on different lymphocyte subsets, with the PI3KÎ´ isoform classically implicated. T-regulatory lymphocytes (Tregs), classically identified by expression of CD4/CD25 and more specifically by expression of FOXP3, are critical in the maintenance of immune self-tolerance and downregulation; they also appear to be instrumental in the mechanism of PI3K-associated autoimmune toxicities. In multiple series, colonic biopsy specimens of patients experiencing idelalisib-associated diarrhea demonstrated intraepithelial lymphocytosis, crypt cell apoptosis, and neutrophilic infiltration.[20,27] In a phase II trial of idelalisib in combination with rituximab, 64% of the enrolled patients experienced diarrhea, and of the 14 patients with diarrhea who underwent colonoscopy, in most a T-cell infiltrate was identified. In addition to the importance of PI3KÎ´ to Treg function, the Î´ isoform plays a role in the differentiation of peripheral T-helper cells into the Th1 and Th2 lineages. Accordingly, in a separate phase II study of the combination of idelalisib and the spleen tyrosine kinase inhibitor entospletinib, high rates of autoimmune pneumonitis were seen, with accompanying increases in the Th1-associated cytokines interferon Î³, interleukin (IL)-6, IL-7, and IL-8 identified in the peripheral blood of affected patients.
Interestingly, younger age and previously untreated disease may be associated with increased risk of autoimmune toxicity. In a phase II trial involving idelalisib in which 79% of subjects experienced transaminase elevation, those who experienced hepatotoxicity had a median age of 61 years, compared with 72 years in those who did not experience hepatotoxicity (P = .02). In patients receiving idelalisib who experienced hepatotoxicity, an increase in proinflammatory cytokines CCL-3 and CCL-4, in addition to a decrease in peripheral blood Tregs, was seen. Liver biopsy samples from affected patients demonstrated an increased infiltrate of activated CD8+ cytotoxic T cells.
Mechanisms of Hypertension, Hyperglycemia, and Neuropsychiatric Effects
PI3K has multiple roles in blood pressure homeostasis,[10,29-31] with the isoform PI3KÎ³ implicated. Angiotensin II has been shown to require PI3KÎ³ to stimulate calcium channels in smooth muscle, resulting in vascular contraction. Additionally, a relationship was found between a single nucleotide polymorphism flanking PIK3CG (which encodes PI3KÎ³) and blood pressure[10,32]; an insulin-dependent vasoconstriction has been proposed as an alternative mechanism for PI3K inhibitor–associated hypertension.[33,34] Clinically, PI3K inhibitor–associated hypertension was demonstrated in 33 patients treated with copanlisib, which has some activity against the Î³ isoform, in addition to preferential activity against the Î± and Î´ isoforms. In this study, hypertension was seen in 70% of patients (49%, grade 3 or higher).
The role of PI3K in glucose homeostasis has also resulted in hyperglycemia being seen with PI3K inhibition, particularly PI3KÎ± inhibition. Alterations in PI3KÎ± signaling are a major contributor to non–insulin-dependent diabetes, and murine models with heterozygous kinase-dead knock-in alleles of p110Î± exhibit glucose intolerance mediated by impaired glucose uptake in muscle and increased hepatic gluconeogenesis.[1,37,38] Clinically, hyperglycemia has been seen with the use of copanlisib, as well as with the pan-isoform PI3K inhibitor buparlisib, with rates of 70% (30%, grade 3 or higher) and 39% (23%, grade 3 or higher) for each agent, respectively.[36,39]
Neuropsychiatric effects such as anxiety and depression were seen in up to one-third of patients receiving buparlisib, with grade 3 or higher confusion seen in up to 10%. The mechanism of these neuropsychiatric effects is less well understood. Buparlisib has been shown to penetrate the blood-brain barrier, and in relapsed/refractory glioblastoma multiforme has demonstrated a clinical benefit rate of 46%.[41,42] The importance of the PI3K/Akt/mTOR pathway has been described in neurologic disorders, but this has been more pertinent in diseases such as dementia, epilepsy, and stroke, because of the pathway’s relationship to cellular survival. However, the pathway has also been shown to play an important role in the protection of neurons from oxidative stress and signal transduction. PI3K/Akt/mTOR signaling has also been implicated in encephalopathy due to sepsis, but this is likely a different mechanism than that involved in the PI3K inhibitor–associated neuropsychiatric symptoms.
Management of Toxicity
Guidelines for the prevention and management of toxicities associated with idelalisib are included in the package insert that comes with the drug, and studies utilizing other PI3K inhibitors currently incorporate close monitoring and management of toxicities associated with this drug class. Expert panel opinion and reviews are available in multiple publications.[24,45] Additionally, idelalisib carries a black-box warning for fatal and/or severe diarrhea/colitis, with risk of intestinal perforation, hepatotoxicity, and pneumonitis. While guidelines have only been established for idelalisib,[11,45] they can reasonably be extrapolated to other PI3K inhibitors as well, as described below. Formal guidelines for the identification and management of additional toxicities associated with less selective PI3K inhibitors will need to be made available to treating providers. We have summarized several key toxicities and suggested management approaches below and in the Table.
Diarrhea and colitis
Immune-mediated colitis from PI3K inhibitors manifests initially as watery, nonbloody diarrhea that does not respond to antimotility agents. Notably, there appear to be two different types of colitis, distinguished by severity and time of onset. An early-onset, less severe diarrhea occurred at a median of 1.9 months after initiation of therapy, while a late-onset, more severe diarrhea occurred at a median of 7.1 months after initiation in trials with idelalisib. All diarrhea that develops while patients are receiving PI3K inhibitors should prompt evaluation for other etiologies-including infection (with consideration of travel history), dietary factors, and medications-followed by diagnostic testing with stool culture, Clostridium difficile testing, and colonoscopy for atypical or refractory cases. Patients with grade 1 or grade 2 diarrhea can continue PI3K inhibitor therapy with dietary optimization (eg, lactose-free, BRAT [bananas, rice, applesauce, toast] diet) and a trial of loperamide, but should be closely monitored and reassessed within 48 hours. PI3K inhibitor therapy should be immediately held in patients experiencing unresolved grade 2 or any episodes of grade ≥ 3 diarrhea, after exclusion of infectious diarrhea; the diarrhea should be treated with budesonide, 9 mg daily, or prednisolone, 1 mg/kg, until symptoms diminish to grade 1 or lower. At that time, lower-dose PI3K inhibition with or without the concomitant use of budesonide can be considered, based on clinical judgment.
Severe autoimmune transaminitis has occurred with idelalisib treatment, and copanlisib use has also been associated with hepatotoxicity, although generally of lesser severity. Guidelines for the management of hepatotoxicity are provided by CoutrÃ© et al, as well as by the package insert for idelalisib.[11,45] In the case of idelalisib, transaminitis most often occurs within the first 12 weeks of initiation of the agent, and should prompt a recommendation for liver function monitoring every 2 weeks for the first 3 months, followed by a schedule of every 4 weeks for the next 3 months and every 1 to 3 months thereafter. If the transaminase elevation is 3 to 5 times the upper limit of normal, idelalisib can be continued at its current dosing, but weekly monitoring of transaminase levels must be performed until normalization. If the alanine aminotransferase or aspartate aminotransferase level is more than 5 times the upper limit of normal, idelalisib should be held, with the potential to restart at a reduced dose once all liver function tests normalize. Patients who experience profound, severe transaminitis (ie, values > 20× the upper limit of normal) should permanently discontinue therapy. We recommend a similar approach for hepatotoxicity associated with other PI3K inhibitors, and recommend close consultation of the package insert and/or investigator brochure for these other agents, as applicable.
Respiratory symptoms and pneumonitis
While mild autoimmune colitis and hepatotoxicity don’t always require immediate cessation of PI3K inhibition, extreme caution should be taken in cases of respiratory symptoms that develop while patients are receiving PI3K inhibitors, due to concerns for autoimmune pneumonitis. Although pneumonitis is less commonly seen (less than 5% of patients) than colitis and hepatotoxicity, even mild respiratory symptoms can quickly progress or lead to permanent deficits in respiratory reserve. Similar to diarrhea, respiratory symptoms should prompt evaluation for an infectious etiology, including opportunistic infections such as PJP. PI3K treatment should be stopped in the event of mild persistent cough, a 5% drop in O2 saturation, dyspnea with exertion, or interstitial infiltrates on imaging. In any patient who develops an oxygen requirement or has a ≥ 5% decrease in baseline O2 saturation, it is recommended that PI3K inhibition be discontinued; that the patient be admitted to the hospital for a workup that should include high-resolution chest CT, with consideration of bronchoscopy/bronchoalveolar lavage; and that empiric prednisone be started at a dose of 1 mg/kg while the patient undergoes an infection workup.[11,24] PI3K inhibition should not be restarted in a patient with suspected autoimmune pneumonitis.
Rashes and cutaneous reactions
Cutaneous reactions, including grade 3 and higher reactions, have been described with idelalisib,[11,45] as well as with other PI3K inhibitors.[25,46] A case of toxic epidermal necrolysis occurred in a study in which idelalisib was combined with bendamustine/rituximab. Other manifestations may include exfoliative dermatitis, various rashes, and other skin disorders.
There are no specific monitoring guidelines available at this time other than what is provided by the FDA prescribing label for idelalisib. We recommend using the Common Terminology Criteria for Adverse Events (CTCAE) published by the National Cancer Institute to describe any cutaneous reactions. For CTCAE grade 1/2 reactions (covering less than 30% of body surface area, with no evidence of superinfection), the recommendation is to monitor closely; for grade 3 or higher reactions (covering more than 30% of body surface area, or with evidence of superinfection), it is recommended that PI3K inhibition be held, and that dermatologic and other experts (including pharmaceutical specialists) be consulted prior to making a decision about reinitiating PI3K inhibition.
Because of the higher rates of opportunistic infections with P jirovecii and CMV seen in clinical trials involving various PI3K inhibitors, infectious monitoring and prophylaxis measures should be considered.[11,13,22,25,48] No PJP-related deaths have occurred in patients receiving PJP prophylaxis; thus, it is now recommended that PJP prophylaxis with trimethoprim/sulfamethoxazole be provided for all patients while receiving PI3K inhibitor treatment. Dapsone or atovaquone can be substituted if a patient is unable to take sulfonamide antibiotics. Empiric treatment for patients who present with pulmonary infiltrates and hypoxia, especially those not receiving prophylaxis, should include treatment for PJP until this etiology is ruled out on bronchoscopy or bronchoalveolar lavage.[11,24,45]
CMV status should be assessed monthly, and patients with symptomatic CMV viremia or end-organ damage (eg, hepatitis, colitis, pneumonitis, retinitis) should discontinue PI3K inhibitor therapy and start antiviral treatment with ganciclovir or valganciclovir. If CMV levels are increasing in asymptomatic patients, consideration can be given to holding idelalisib and starting empiric ganciclovir or valganciclovir.[24,45]
- Phosphatidylinositol 3-kinase (PI3K) inhibitors are effective treatments for B-cell malignancies, but many have unique toxicities based on the differential expression of the four different PI3K isoforms (Î±, Î², Î´, Î³) in different body tissues and organs.
- Unique toxicities include autoimmune effects (colitis, hepatitis, pneumonitis, rash), opportunistic infections (cytomegalovirus, Pneumocystis jirovecii pneumonia), hypertension, hyperglycemia, and neuropsychiatric changes. Inhibition of different PI3K isoforms is associated with different toxicities.
- Many toxicities associated with PI3K inhibitors can be effectively managed while continuing treatment, while others require discontinuation of the causative agent. Prompt attention to reported toxicities and adherence to prescribing information and expert guidelines are essential for patients using these therapies.
Significant rates of grade 3 or higher hypertension have been seen with the Î±/Î´ isoform–predominant PI3K inhibitor copanlisib, as described previously. Recommendations from the FDA package insert provide guidance on management of copanlisib-associated hypertension. Notably, copanlisib is administered IV on days 1, 8, and 15 of a 28-day cycle, as opposed to the twice-daily continuous oral dosing of idelalisib. Given the differences in monitoring between intermittent IV and continuous oral administration, some clinical judgment will be required for extrapolation of guidelines to other agents in development. For copanlisib, guidelines recommend withholding administration for any pre-dose blood pressure of 150/90 mm Hg or higher until blood pressure is lowered to less than 150/90 mm Hg on two consecutive measurements at least 15 minutes apart. For post-dose blood pressure of 150/90 mm Hg or higher requiring antihypertensive treatment, the prescribing information recommends consideration of a dose reduction, and if there are life-threatening consequences, recommends discontinuation of copanlisib.
Other PI3K inhibitors in development may be administered daily by mouth, as opposed to weekly IV. Adaptation of recommendations for other targeted agents, such as those for some angiogenesis inhibitors, can also be considered. Blood pressure should be controlled (< 140/90 mm Hg) prior to initiation of treatment and should be monitored during the first week of therapy. For grade 2 (140–159/90–99 mm Hg) PI3K inhibitor–related hypertension, initiation of antihypertensive therapy with an appropriate agent is indicated, taking into account any other comorbidities the patient may have. For grade 3 hypertension (> 160/100 mm Hg, but no evidence of end-organ damage or life-threatening consequence), initiation of antihypertensives with early follow-up (no later than 1 week) should occur. Severe hypertension (> 200/110 mm Hg) or evidence of end-organ damage should prompt immediate discontinuation of therapy and strong consideration of admission to an inpatient setting until blood pressure control can be achieved. Blood pressure goals should also take into account any existing comorbidities (eg, coronary artery disease, diabetes) and severe thrombocytopenia that would predispose to hypertensive hemorrhage.
Other management strategies, including monitoring for proteinuria or other signs of end-organ damage, home blood pressure monitoring, and ruling out other causes of hypertension (such as an infusion reaction), should be considered as well.
Hyperglycemia has been seen with use of some agents, particularly the Î±/Î´ inhibitor copanlisib (administered IV) and the pan-inhibitor buparlisib (administered orally). Once agents are FDA-approved, specific guidelines based on trial experience will likely be provided. Recommendations from the FDA prescribing information provide guidance on hyperglycemia in the setting of copanlisib use. Copanlisib should be held for pre-dose fasting blood glucose levels of ≥ 200 mg/dL. If pre-dose or post-dose glucose levels are found to be ≥ 500 mg/dL, copanlisib should be decreased from 60 mg to 45 mg at first occurrence, decreased from 45 mg to 30 mg on second occurrence, and discontinued if elevated levels persist at a dose of 30 mg.
Other general recommendations prior to initiation of PI3K inhibitors with a known association of hyperglycemia include screening patients for a history of diabetes or insulin resistance. In our experience, if a patient has a diagnosis of diabetes, comanagement of his or her blood sugar should be instituted with the patient’s primary care provider or endocrinologist. Patients with uncontrolled diabetes are typically not candidates for therapy with PI3K inhibitors that are known to cause hyperglycemmia. Dose reductions of PI3K inhibitors will be drug-specific. Switching to an alternate PI3K inhibitor (or an alternate drug class) can be considered if an appropriate FDA-approved agent is available.
Anxiety, depression, and confusion have been seen with PI3K inhibitors, particularly with buparlisib.[26,41] In our experience, most events have been reversible and generally mild-to-moderate mood alterations, and many of the affected patients had a history of depression and/or anxiety. Care should be taken to screen for a psychiatric history, with special attention to any history of bipolar disorder or depression. Patients should also be screened routinely for changes in mood or for thoughts of suicide or homicide.
If patients experience grade 2 or higher mood or neuropsychiatric symptoms, their PI3K inhibitor should be held and they should be evaluated by a psychiatrist, with consideration given to initiation of an appropriate psychiatric medication, such as a selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor. Tools such as the Patient Health Questionnaire-9 (PHQ-9; for depression) or Generalized Anxiety Disorder 7-Item Scale (GAD-7; for anxiety) can be used to quantify the degree of neuropsychiatric alteration. Thoughts of suicidal ideation or homicidal ideation should prompt immediate psychiatric evaluation.
PI3K inhibition has become an important strategy in the management of hematologic malignancies, but has been associated with some unusual toxicities that arise as a result of inhibition of the PI3K pathway in nonmalignant cells. Knowledge of the pathway, isoforms, and distribution of the various isoforms in tissues can help clinicians anticipate toxicities. While the PI3KÎ´ inhibitors idelalisib and copanlisib are currently the only FDA-approved PI3K inhibitors to date, multiple other inhibitors of various isoforms are undergoing phase III testing. Knowledge of the toxicity profiles of different inhibitors can help clinicians determine which agents would likely be best tolerated, given a patient’s comorbidities or previous PI3K inhibitor intolerance. This is demonstrated by an interesting trial (currently accruing) that is looking at use of the PI3KÎ´ inhibitor umbralisib in individuals previously intolerant to prior Bruton tyrosine kinase or PI3KÎ´ inhibitory therapy. As additional PI3K inhibitors become available, it will be important to anticipate and screen for expected and unexpected toxicities associated with these agents. However, as long as these drugs are used within the prescribing guidelines, they have generally been found to provide a combination of tolerability and efficacy not seen with many previous cytotoxic therapies.
Financial Disclosure:Dr. Cohen has received research funding from Novartis for the investigation of buparlisib, and has received grant support from the Lymphoma Research Foundation and the American Society of Hematology. Drs. Greenwell and Ip have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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